期刊
HYPERTENSION
卷 53, 期 2, 页码 404-408出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.108.124339
关键词
fetal programming; hypertension; renin-angiotensin system; sheep; angiotensin-converting enzyme 2; proximal tubules and serum
资金
- NHLBI NIH HHS [HL-51952, R29 HL056973, R01 HL056973, P01 HL051952-150007, HL-56973, R01 HL056973-09, P01 HL051952] Funding Source: Medline
- NICHD NIH HHS [R01 HD017644-23, HD-47584, P01 HD047584-04, HD-17644, P01 HD047584, R01 HD017644] Funding Source: Medline
Antenatal betamethasone treatment is a widely accepted therapy to accelerate lung development and improve survival in preterm infants. However, there are reports that infants who receive antenatal glucocorticoids exhibit higher systolic blood pressure in their early adolescent years. We have developed an experimental model of programming whereby the offspring of pregnant sheep administered clinically relevant doses of betamethasone exhibit elevated blood pressure. We tested the hypothesis as to whether alterations in angiotensin-converting enzyme (ACE), ACE2, and neprilysin in serum, urine, and proximal tubules are associated with this increase in mean arterial pressure. Male sheep were administered betamethasone (2 doses of 0.17 mg/kg, 24 hours apart) or vehicle at the 80th day of gestation and delivered at term. Sheep were instrumented at adulthood (1.8 years) for direct conscious recording of mean arterial pressure. Serum and urine were collected and proximal tubules isolated from the renal cortex. Betamethasone-treated animals had elevated mean arterial pressure (97 +/- 3 versus 83 +/- 2 mm Hg; P < 0.05) and a 25% increase in serum ACE activity (48.4 +/- 7.0 versus 36.0 +/- 2.7 fmol/mL per minute) but a 40% reduction in serum ACE2 activity (18.8 +/- 1.2 versus 31.4 +/- 4.4 fmol/mL per minute). In isolated proximal tubules, ACE2 activity and expression were 50% lower in the treated sheep with no significant change in ACE or neprilysin activities. We conclude that antenatal steroid treatment results in the chronic alteration of ACE and ACE2 in the circulatory and tubular compartments, which may contribute to the higher blood pressure in this model of fetal programming-induced hypertension. (Hypertension. 2009; 53[part 2]: 404-408.)
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